So-called “an in-water drying method” is known as one of the methods for preparation of microsphere, which comprises dispersing an organic phase prepared by dissolving a hardly-water-soluble polymer in a water-immiscible organic solvent having a boiling point lower than that of water in an aqueous phase to prepare an O/W type emulsion, and thereafter removing the organic solvent (cf, for example, JP-B-56-19324; JP-A-63-91325; JP-A-8-151321; Kajeev Jain et al., “Controlled Drug Delivery by Biodegradable Poly (Ester) Devices: Different Preparative Approaches”, Drug Development and Industrial pharmacy, vol. 24 (No. 8), pp. 703–727, 1998; JP-A-60-100516; JP-A-62-201816; JP-A-9-221417; and JP-A-6-211648).
This in-water drying method includes a problem of removal of the organic solvent in view of environmental pollution.
For example, it is known a method comprising emulsifying a drug-containing solution of a polymer in methylene chloride in an aqueous phase and then removing the organic solvent by stirring the emulsion as it stands at room temperature for a long period of time (cf., JP-A-9-221417, etc.), but according to this method, the methylene chloride is released in the air through the aqueous phase.
A regulation for prevention of environmental pollution is issued by Kanagawa Prefecture, whereby the concentration of methylene chloride at an exhaust port of a factory is regulated less than 50 ppm (cf., “A Handbook for Proper Use of Chlorocarbons” issued by Chlorocarbon Sanitary Society, 1996), and further organic solvents such as methylene chloride, chloroform are defined as class I chemical substance which shall be well controlled by the industrial companies by “A law in regard to monitor of the discharging amount etc. of specific chemical substances into environment and improvement of control thereof” published on Jul. 13, 1999 as well as by an Order of the Government issued on Mar. 29, 2000.
Accordingly, when organic solvents such as methylene chloride are used on an industrial scale, it is required to treat it by using an apparatus in a closed system so that the discharge thereof into outside shall be well controlled in view of environmental problem.
Moreover, where the produced microspheres are used as a medicament (particularly, parenteral utilization such as injection, depots), it is essential to sterilize in the step of preparation thereof and it is required to prepare the microspheres in a closed system so as to prevent from contamination of microbes outside.
For a method for controlling the discharge of organic solvents, it has been studied to prepare microspheres in a closed system. For example, a method was proposed where the contact area of an outer aqueous phase and a gaseous phase as well as the rate of circulation and stirring speed of an emulsion are controlled and further a gas is blown onto the emulsion in order to increase the moving speed of gas at the surface of the emulsion (cf., JP-A-9-221418).
However, by the method of blowing of gas onto the surface, the surface area of the emulsion to be contacted with the gas is limited, and hence, it is not enough to remove efficiently the organic solvent for practical use, and further it has very low efficiency of the removal of organic solvent so that a large amount of the aqueous phase is required in order to prevent coagulation of the emulsion. Thus, this method has a problem that it is difficult to miniaturize the apparatus for the preparation of microspheres.
On the other hand, it is also proposed to use a polymer membrane for the purpose of disposal of waste water and recovery of vapor of organic solvent (cf., Ind. Eng. Chem. Res., vol. 32, p. 533, 1993), and there have been found some membranes for separation and recovery of chlorine organic solvents (cf, JP-A-5-15749, JP-A-6-55166, JP-A-7-284641, JP-A-8-57274, JP-A-9-117642).